The present invention relates to fibers for encapsulating and delivering drugs, and more specifically, to cationic fibers formed by self-assembly of cationic compounds for reversible binding and controlled release of hydrophobic anionic drugs.
The majority of clinically used drugs are low molecular weight compounds that are characterized by short half-life in the blood stream, high clearance rate, limited solubility, limited stability, and/or high toxicity. A number of drug delivery systems have been proposed to overcome one or more of these drawbacks including liposomes, microspheres, virosomes, nanocrystals, nanotubes and electrospinning. For example, when treating cancerous tumors, efficient drug delivery requires novel nanocarriers that have a hydrophilic shell to prevent protein adsorption, thereby prolonging blood circulation, and a hydrophobic core for loading (typically hydrophobic or moderately polar) drugs. Nanosize allows passive targeting into tumor tissue based on the enhanced permeability and retention (EPR) effect. Ideal nanocarriers should possess one or more, and preferably all, of the following properties: 1) biodegradability and biocompatibility; 2) high loading capacity for various drugs; 3) kinetic stability after injection into the blood stream; 4) narrow size distribution for desirable and uniform biodistribution, and 5) biological ligands for active targeting to tumor tissues.
Polymer therapeutics includes polymer/drug complexes (in which the polymer acts as a sequestrant for the drug), covalently bound polymer-drug conjugates, covalently bound polymer-protein conjugates, non-covalently bound polymer-DNA complexes (polyplexes), and polymeric micelles to which drugs are covalently bound and/or physically incorporated. Conventionally, nanoscale therapeutics are derived from polymer-drug (or polymer-protein) conjugates, in which a drug is covalently linked to a polymer through a cleavable linker such as a lysosome-dependent Gly-Phe-Leu-Gly tetrapeptide and pH sensitive cis-aconityl, hydrazone, or acetal linkages. Alternatively, supramolecular drug delivery systems are based on the assembly of block copolymer into micelles and partitioning of drug into the micelle interior. Dendritic polymer nanocarriers also show promise for tumor targeting and drug delivery. Both covalent and non-covalent systems can utilize the enhanced permeability and retention effect in disorganized and leaky angiogenic tumor vasculature for targeting.
Self-assembled block copolymer micelles are typically several tens of nanometers in diameter with a relatively narrow size distribution and have long been explored because they are expected to be a simple, economic and a versatile approach to nanosized drug carriers. The major obstacles for supramolecular drug-delivery systems based on non-covalent entrapment of drugs into core-shell architectures are the lack of kinetic stability of polymer micelles that are susceptible to infinite dilution arising from their administration and poor drug loading capacity. Critical micelle concentration (CMC) of polymers is an important parameter to anticipate in vivo kinetic stability of the micelles. Efforts to bolster the weak intermolecular interactions that effect micelle formation and stability include selective crosslinking of either the interior (core) or exterior (corona), crosslinking throughout the micelle, and/or stabilizing non-covalent interactions. Despite the improved stability of the chemical cross-linking, this approach may not be optimal for the encapsulation of a guest molecule or for biodegradability. The precisely-tunable structure of block copolymers combined with new synthetic methodologies can allow the use of non-covalent interactions in polymeric assemblies. The role of non-covalent interactions is particularly pronounced as a collective driving force to the formation of stable aggregates as well as micelle-drug interactions. For example, Giacomelli, et al., Langmuir 2007, volume 23, pages 6947-6955 reported that specific acid-base interaction between hydrophobic drug molecules (R1—COOH) and polymer segments (H2N—R2) improved the drug loading capacity of block copolymer micelles.
Another class of drug delivery macromolecules with well-defined architecture is branched polymers including dendrimers and hyperbranched polymers. Dendrimer structure was first reported in the 1980s. The unique architecture of dendrimers offers advantages including presentation of high local concentration of desired functionality (such as positive charges, targeting groups, and hydrophilic groups for water solubility) on the periphery of the molecules. This core/shell structure serves as the main principle of their drug sequestration either by physical or chemical attachment. Dendrimers are often synthesized either by divergent growth from the initiator core to the targeted generation, or from the periphery inward, terminating at the core, known as the convergent method. While the divergent method normally produces dendrimers with symmetrical architecture, the convergent method allows one to synthesize dendrimers with different dendritic segments or layers of functionalities. The most commonly studied dendrimers for medical applications include polyamidoamine (PAMAM), polypropyleneimine (PPI), dendrimers and hyperbranched polymers derived from bis(hydroxymethyl)propionic acid, carbosilane dendrimer, and branched-peptides or dendritic peptides from an L-lysine core.
A key advantage of dendrimers over a polymeric sequestrant or a micelle is the absence of polydispersity in molecular weight. Dendrimers are molecules with exact molecular weights, which from a regulatory point of view, minimizes the complexities associated with polymers. Moreover, the low polydispersity should provide reproducible pharmacokinetic behavior in contrast to a polymer that contains significant distribution in molecular weights. Limitations of dendrimers may include the cost of synthesis, limited cargo space and small size which may allow them to randomly “leak” through the vascular wall. With this in mind, there is a need to devise a strategy to preserve the multivalency associated with dendrimers but increase the particle size. In part this has been accomplished using dendritic-linear or dendritic-star hybrids. Although this accomplishes part of the goal, it reintroduces the issue of molecular weight dispersity.
Therefore, a clear need exists for a drug delivery vehicle that has an exact molecular weight, high multivalency, and the appropriate size and functionality to allow long circulation times.